Comparison of cumulative clinical benefits of biologics for the treatment of psoriasis over 16 weeks: Results from a network meta-analysis.

BACKGROUND: Cumulative clinical improvement and speed of improvement are important to psoriasis patients. OBJECTIVE: Compare cumulative benefits of biologics over 12 to 16 weeks in the treatment of moderate to severe psoriasis. METHODS: A systematic literature review identified phase III trial data on Psoriasis Area and Severity Index (PASI) responses for biologics during 12 and 16 weeks of treatment. Cumulative clinical benefit, measured by the area under the curve for PASI ≥75% improvement (PASI 75), ≥90% improvement (PASI 90), and 100% improvement (PASI 100), was compared using the network meta-analysis and Bayesian methodology on the relative probability of achieving percentage of maximum area under the curve. RESULTS: Among biologics approved for psoriasis treatment, anti-interleukin-17 biologics demonstrated consistently greater cumulative clinical benefits on PASI 75, PASI 90, and PASI 100 over the 12- or 16-week period than anti-interleukin-23 and other biologics. For biologics with 12-week data, ixekizumab and brodalumab showed greater cumulative benefits for PASI 75, PASI 90, and PASI 100 than secukinumab, followed by guselkumab, infliximab, adalimumab, ustekinumab, and etanercept. Ixekizumab showed greater cumulative benefits than all other biologics reporting 16-week data. LIMITATIONS: Recently approved biologics were not included. CONCLUSION: Ixekizumab (at 12 weeks and 16 weeks) and brodalumab (at 12 weeks) had greater cumulative clinical benefit than all of other biologics studied.

Detection and prediction of periodic patterns by the retina.

A fundamental task of the brain is detecting patterns in the environment that enable predictions about the future. Here, we show that the salamander and mouse retinas can recognize a wide class of periodic temporal patterns, such that a subset of ganglion cells fire strongly and specifically in response to a violation of the periodicity. This sophisticated retinal processing may provide a substrate for hierarchical pattern detection in subsequent circuits.

Early Treatment Targets for Predicting Long-term Dermatology Life Quality Index Response in Patients with Moderate-to-Severe Plaque Psoriasis: A Post-hoc Analysis from a Long-term Clinical Study.

BACKGROUND: Rapid improvements in health-related quality of life (HRQoL) and psoriasis severity have been reported in patients treated with ixekizumab (IXE), an interleukin (IL)-17A antibody. OBJECTIVE: We assessed the relationship between early Psoriasis Area and Severity Index (PASI) response and long-term Dermatology Life Quality Index (DLQI) improvement in patients in the randomized clinical trial IXORA-S (NCT0256186) treated with IXE or IL-12/23 (ustekinumab [UST]). METHODS: The proportion of patients achieving DLQI (0,1), an outcome equivalent to the patient's skin condition having no impact on HRQoL after 52 weeks of IXE or UST by PASI response at Weeks 4, 12, and 24 was quantified. Optimal thresholds for PASI response by treatment to predict Week 52 DLQI (0,1) were calculated based on Youden's Index. RESULTS: Early and higher levels of skin clearance were associated with improved patient outcomes regardless of treatment. Patients treated with IXE achieved faster and more pronounced PASI response than patients treated with UST. The optimal thresholds at Weeks 4, 12, and 24 for predicting DLQI (0,1) at Week 52 were ~PASI 75 for IXE versus ~PASI 50 for UST at Week 4, PASI 90 for IXE versus PASI 75 for UST at Week 12, and ~PASI 100 for IXE versus ~PASI 90 for UST at Week 24. Among patients achieving these thresholds, the probability of achieving a DLQI (0,1) was significantly higher. CONCLUSION: Earlier and higher levels of skin clearance are associated with improved patient outcomes over the long term, regardless of treatment.

Greater cumulative benefits from ixekizumab versus ustekinumab treatment over 52 weeks for patients with moderate-to-severe psoriasis in a randomized, double-blinded phase 3b clinical trial.

Background: Ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets interleukin-17A, has shown superiority to ustekinumab (UST) and etanercept in skin clearance from randomized clinical trials in patients with moderate-to-severe psoriasis.Objective: To compare cumulative benefits of IXE versus UST over 52 weeks of treatment.Methods: Cumulative clinical benefit of IXE and UST was assessed by evaluating the area under the curve (AUC) for responders of Psoriasis Area and Severity Index (PASI), itch numeric rating scale (Itch NRS), and Dermatology Life Quality Index (DLQI) outcomes over 52 weeks using data from IXORA-S trial comparing IXE (N = 136) and UST (N = 166). Normalized cumulative benefit was calculated to obtain the percentage of the maximum AUC for each outcome measure. Missing values were imputed using non-responder imputation.Results: Significantly greater cumulative benefits were obtained for IXE compared with UST. Normalized cumulative benefit with IXE versus UST for PASI 75/90/100, Itch NRS (0), and DLQI (0,1) were 83.1% and 67.6%; 68.9% and 46.5%; 41.1% and 23.4%; 40.4% and 30.9%; and 62.2% and 46.6%, respectively. Cumulative clinical benefit ratios for IXE:UST were 1.23 for PASI 75, 1.48 for PASI 90, and 1.76 for PASI 100, indicating an increase in the cumulative clinical benefit for IXE versus UST as the clearance levels increased.Conclusions: IXE showed greater cumulative clinical benefit than UST.

Efficacy and Safety of Ixekizumab Through 5 Years in Moderate-to-Severe Psoriasis: Long-Term Results from the UNCOVER-1 and UNCOVER-2 Phase-3 Randomized Controlled Trials.

INTRODUCTION: Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A, is approved for treatment of moderate-to-severe plaque psoriasis. Our objective was to evaluate the long-term efficacy and safety of ixekizumab in moderate-to-severe plaque psoriasis through 5 years. METHODS: Data were integrated from the UNCOVER-1 and UNCOVER-2, randomized, double-blinded, phase-3 trials. Patients who continuously received the labeled ixekizumab dose, were static Physician's Global Assessment (sPGA) (0,1) responders at Week 12 and completed 60 weeks of treatment could enter the long-term extension (LTE) period. Patients could escalate to every-2-week dosing per investigator opinion. Efficacy and health outcomes included proportion of patients achieving Psoriasis Area and Severity Index (PASI) 75/90/100, sPGA (0,1) and (0), absolute PASI ≤ 5/ ≤ 3/ ≤ 2/ ≤ 1 and Dermatology Life Quality Index (DLQI) (0,1). Results exclude patients who escalated to every-2-week dosing. A modified non-responder imputation method was used to account for missing data. Supplemental analyses include patients who escalated to every-2-week dosing and observed and multiple imputation results. Exposure-adjusted safety outcomes are also reported. RESULTS: Of 206 patients who entered the LTE periods, 172 completed treatment. At Week 60, PASI 75/90/100 responses were 94.7%, 85.0% and 62.1%, respectively, and at year 5 were 90.3%, 71.3% and 46.3%, respectively. Similarly, meaningful responses were achieved for the other efficacy and health measures. Among patients with PASI 100 through 5 years, 92% achieved DLQI (0,1), indicating no impact of skin disease on quality of life. During the LTE period, exposure-adjusted incidence rates were 31.4 per 100 patient-years for treatment-emergent adverse events and 6.8 per 100 patient-years for serious adverse events. No deaths were reported. No new or unexpected safety findings were noted. CONCLUSIONS: The results demonstrate 80 mg ixekizumab maintains long-term efficacy and a safety profile consistent with previous data in patients with moderate-to-severe plaque psoriasis through 5 years of treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier, UNCOVER-1: NCT01474512, UNCOVER-2: NCT01597245.

Patient Perspective on the Burden of Skin and Joint Symptoms of Psoriatic Arthritis: Results of a Multi-National Patient Survey.

INTRODUCTION: Psoriatic arthritis (PsA) and psoriasis (PsO) have a significant impact on HRQOL and work productivity loss. In patients with both PsA and PsO, the full extent of the physical and emotional burden of joint- and skin-related symptoms is less understood from the patient perspective. METHODS: A cross-sectional study of PsO patients with PsA from the US, France, and Germany was conducted using an online survey. Data on demographics, PsO severity by patient-reported body surface area involvement (BSA), PsA severity by RAPID3, impact of PsO and PsA using Patient Global Assessment (1-5), and novel questions exploring the emotional burden of joint/skin-related symptoms were collected. Multivariate regression analyses examined severity of joint and skin symptoms as predictors of quality of life (QoL), measured by PsAQoL, and Work Productivity and Activity Impairment (WPAI). RESULTS: Of the 439 patients, 23.9% had mild (RAPID3 of 0-2) and 76.1% had moderate-severe PsA (RAPID3 of 2.1-10), while 51% had mild and 49% had moderate-severe PsO (≥ 3 palms of the hand for BSA). Multivariate analyses showed that severity of joint symptoms was strongly associated with lower QoL (t = 13.15), followed by impact of skin symptoms (t = 5.11), and age (t = - 4.73), all p < 0.0001. About 57% of all patients reported a DLQI > 5, indicating a moderate-to-extremely large effect of psoriasis on HRQoL. Joint severity and impact of joint symptoms were the strongest predictors of WPAI. Patients also associated skin and/or joint symptoms with a variety of emotions and QoL measures that were not captured on the validated scales (fatigue, how they think of themselves, how others thought of them, making a first impression etc.). CONCLUSIONS: In this study, both skin and joint symptoms had a broad, meaningful impact on patient QoL, work productivity, daily activities, and emotional well-being. These data highlighted the unique and significant impact of PsA among patients with PsO. FUNDING: Eli Lilly and Company.

Understanding Treatment Preferences in Patients with Moderate to Severe Plaque Psoriasis in the USA: Results from a Cross-Sectional Patient Survey.

INTRODUCTION: The goal of psoriasis (PsO) treatment is to improve quality of life by lessening the extent and severity of the disease. Traditional systemic drugs and biologic agents are used for the treatment of moderate to severe PsO and recent research emphasizes understanding patient goals and preferences for treatment, to improve overall outcomes. METHODS: An online survey was administered to collect data from 500 adult patients with moderate to severe PsO in the USA. Patients were required to have current or previous systemic therapy use and were excluded if aged 75 or older. Data on demographics, disease burden, treatment use, and patients' treatment goals and expectations were collected. Descriptive and multivariate analyses examined the factors that predict treatment goals. Subgroup analyses were performed for age, gender, severity, comorbid psoriatic arthritis (PsA), location of PsO, and biologic experience. All analyses were conducted using SAS v9.4 and R v3.4. RESULTS: Of the 500 adult patients included, 71.6% reported moderate PsO. Patients had a mean (SD) score of 62.4 (23.0) for skin pain, 60.0 (26.3) for fatigue, and 6.6 (2.1) for itch on a scale of 0-100, 0-100, and 0-10 respectively. Mean (SD) score for quality of life (QoL), assessed using Dermatology Life Quality Index (DLQI), was 18.3 (7.3), with more than 90% having moderate/very large/extremely large effect on life. The majority of patients considered "keeping skin clear for 2-3 years" (94%), "overall relief of symptoms" (93.8%), and effective in clearing certain areas" (92.2%) as important attributes of a systemic treatment. Overall, patients expected 50% clear skin in about 2 weeks and completely clear skin in about 4 weeks. CONCLUSIONS: Overall, in this study with more than 70% of patients with moderate disease, patients reported high burden of disease and impact on QoL. This study demonstrates the importance of considering patient perspectives in treatment decisions that are critical for optimizing patient outcomes. FUNDING: Eli Lilly and Company.

Ixekizumab and complete resolution of enthesitis and dactylitis: integrated analysis of two phase 3 randomized trials in psoriatic arthritis.

BACKGROUND: Ixekizumab improves signs/symptoms of psoriatic arthritis (PsA). We present an integrated analysis of baseline disease burden and post-baseline outcomes in ixekizumab-treated patients with enthesitis or dactylitis. METHODS: Data from SPIRIT-P1 and SPIRIT-P2 were integrated. Patients with PsA were randomized to 80-mg ixekizumab every 4 weeks (IXEQ4W) or 2 weeks (IXEQ2W), after a 160-mg starting dose, or to placebo. Inadequate responders at week 16 received rescue therapy. Among patients with baseline enthesitis (Leeds Enthesitis Index [LEI] > 0) or dactylitis (Leeds Dactylitis Index-Basic [LDI-B] > 0), baseline characteristics and disease burden were reported. At week 24, LEI and LDI-B (percentage of patients with resolution [LEI = 0, LDI-B = 0]) were assessed. In pooled treatment groups, the impact of enthesitis or dactylitis resolution on health-related quality of life (HRQoL) (EuroQol-5 Dimensions Visual Analogue Scale [EQ-5D VAS]), physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI]), and pain was assessed. RESULTS: The integrated analysis set comprised 679 patients; of these, 60% (n = 403 of 675) had baseline enthesitis (LEI > 0) and 23% (n = 155 of 676) had baseline dactylitis (LDI > 0). At week 24, ixekizumab-treated patients experienced significantly more resolution than placebo of enthesitis (39% IXEQ4W, 35% IXEQ2W, 21% placebo) and dactylitis (78% IXEQ4W, 65% IXEQ2W, 24% placebo). Furthermore, at entheseal points measured by the LEI, ixekizumab-treated patients had significantly higher resolution of enthesitis compared to placebo. At week 24, among all placebo- and ixekizumab-treated patients, resolution of enthesitis was associated with improvements in function and HRQoL whereas dactylitis resolution was associated with more limited improvements. The least squares mean HAQ-DI improvements from baseline were - 0.44 and - 0.25 for patients who did/did not resolve enthesitis, and - 0.41 and - 0.31 for patients who did/did not resolve dactylitis. EQ-5D VAS improvements were 12.3 and 5.8 for patients who did/did not resolve enthesitis, and 10.8 and 9.8 for patients who did/did not resolve dactylitis. CONCLUSIONS: Among patients with pre-existing enthesitis or dactylitis, IXEQ2W- and IXEQ4W-treatment resulted in significant improvements in enthesitis and dactylitis. Enthesitis resolution was associated with improvements in patients' function, pain, and HRQoL. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01695239 , registered on September 25, 2012, and NCT02349295 , registered on October 10, 2014.

Usability of a novel disposable autoinjector device for ixekizumab: results from a qualitative study and an open-label clinical trial, including patient-reported experience.

BACKGROUND: Most biologic therapies for psoriasis are delivered via subcutaneous injection. Ixekizumab, an anti-interleukin 17A monoclonal antibody approved for patients with moderate-to-severe plaque psoriasis, is delivered subcutaneously via prefilled syringe or autoinjector. Here we report the results of an ixekizumab autoinjector usability study as well as the patient-reported experience with the autoinjector in a clinical trial. METHODS: The usability study enrolled 49 subjects (patients with a range of autoimmune conditions or their caregivers). Subjects were randomized to a trained or untrained group and were evaluated for their ability to perform an injection successfully when provided the device and the instructions for use. In the clinical trial, 102 subjects (patients with psoriasis or their caregivers) used the autoinjector to deliver injections of ixekizumab (80 mg every 2 weeks after a starting dose of 160 mg). At weeks 0, 4, and 8, subjects completed the subcutaneous administration assessment questionnaire, which assesses the ease of use and confidence with using an injection device. RESULTS: In the usability study, all subjects in the untrained arm performed successful injections, while two subjects in the trained arm had an injection failure. These incidences were not consistent with any pattern of issues with the device or the instructions for use. In the clinical trial, there were two injection failures of 674 total self-injections performed over 12 weeks. At the first use of the device, 95% of subjects either agreed or strongly agreed that the device was "overall easy to use", and they felt "confident the dose was complete" according to the subcutaneous administration assessment questionnaire. CONCLUSION: The ixekizumab autoinjector was used successfully by patients and caregivers with or without training. Subjects using the autoinjector in a clinical trial felt it was easy to use and felt confident while using it.

Does A1c consistently reflect mean plasma glucose?

BACKGROUND: A1c, a surrogate measure of glycemic control, is known to have a strong linear correlation with mean plasma glucose (MPG) when analyzed in populations of patients. However, clinically significant intersubject variability in this relationship exists, which suggests that A1c measurements may not reflect actual glycemic control in some patients. In the present study we explored the extent to which A1c accurately represents glycemic control, as measured by MPG, for individual patients. METHODS: Data were pooled from randomized clinical trials in which A1c and self-monitored plasma glucose (SMPG) profiles were collected by patients with Type 2 diabetes treated with insulin analog regimens. MPG levels were calculated from SMPG profiles. Distributions of MPG were analyzed for patients within similar ranges of A1c (<6.5%, 6.5%-<7.5%, 7.5%-<8.5%, 8.5%-<9.5%, and ≥9.5%) and distributions of A1c were analyzed in patients within similar ranges of MPG (<6.1, 6.1-<7.8, 7.8-<9.4, 9.4-<11.1, and ≥11.1 mmol/L). RESULTS: Substantial proportions of patients had clinically significant differences between A1c and MPG. For example, among 260 patients with A1c between 6.5% and 7.5%, 10% had MPG levels <6.4 mmol/L, whereas 10% had MPG >9.5 mmol/L. Among the 224 patients with MPG levels ≥6.1 mmol/L and <7.8 mmol/L, 10% had A1c <6% and 10% had A1c >8.1%. CONCLUSIONS: In the absence of SMPG, A1c may inadequately represent glycemic control for many diabetic patients.

Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer's presenilin-1 and presenilin-2.

Early-onset familial Alzheimer's disease is the most aggressive form of Alzheimer's, striking patients as early as their 30s; those patients typically carry mutations in presenilin-1 and presenilin-2. To investigate the coordinated functions of presenilin in the adult brain, we generated double knockout mice, in which both presenilins were deleted in the forebrain. We found that concurrent loss of presenilins in adulthood resulted in massive cortical shrinkage, atrophy of hippocampal molecular layers and corpus callosum, and enlargement of the lateral and third ventricles. We further revealed that deficiency of presenilins caused a series of biochemical alterations, including neuronal atrophy, astrogliosis, caspase-3-mediated apoptosis, and tau hyperphosphorylation. Thus, our study demonstrates that presenilins are essential for the ongoing maintenance of cortical structures and function.